The Principal Investigator, Dr. Joseph El Youssef, under the mentorship of Drs. Kenneth Ward, Andrew Ahmann and Charles Roberts at the Oregon Health and Science University (OHSU), will undertake the project entitled "Optimization of an Adaptive Dual-Hormone External Endocrine Pancreas". Utilizing the services of the Oregon Clinical and Translational Research Institute (OCTRI), and the Department of Comparative Medicine at OHSU, Dr. El Youssef intends to improve the efficiency of an adaptive closed loop system which automatically delivers insulin and glucagon subcutaneously to persons with diabetes in response to glucose levels obtained by subcutaneously inserted continuous glucose monitors. These studies will assist in the progression of his clinical research skills, supplemented by an OHSU course in the Human Investigation Program (HIP) certificate program, designed to educate and develop young investigators in clinical and translational research. Dr. El Youssef will design and carry out animal studies geared towards testing the pharmacokinetic and dynamic properties of novel preparations of insulin and glucagon, in order to improve closed-loop glycemic control. In addition, Dr. El Youssef will develop skills in computer programming and control theory, with classes at Portland State University and at the Rensselaer Polytechnic Institute in Troy, NY, taught by long-term collaborator Dr. Wayne Bequette, who will also provide instruction in control theory and the software tools needed for modeling and simulation. These courses will provide Dr. El Youssef with experience in algorithm development and system modeling, important requirements for independent progression in this field. Mr. John Lum at the Jaeb Center for Health Research has agreed to collaborate with Dr. El Youssef, providing access to the FDA-approved 300 person simulator for testing of algorithm updates, with which Dr. El Youssef is familiar. The clinical aspect of the proposal is to successively refine iterations of the Adaptive Proportional Derivative algorithm in persons with Type 1 diabetes over the five years of the mentored project. The anticipated improvements in the closed loop glycemic control system will include: (a) adapting the system for corticosteroid-induced insulin resistance and for exercise-induced increases in insulin sensitivity;(b) reducing pre-meal open-loop insulin delivery by creating a "meal mode" component designed for use with a faster-onset zinc-free insulin preparation (Linjeta, from Biodel, Inc);(c), developing a total-body glucagon model and incorporating it into the algorithm to optimize the way in which the algorithm calls for glucagon delivery in order to maximize hypoglycemia prevention and to minimize hepatic glycogen depletion. Appropriately-powered studies in subjects with Type 1 diabetes will address each of these questions. As this mentored project comes to a close, Dr. El Youssef will become an independent researcher in diabetology, with a focus on closed-loop insulin/glucagon delivery systems, and developing into a physician-scientist who can provide ongoing contributions in the field of automated glycemic control in persons with Type 1 diabetes. PUBLIC HEALTH RELEVANCE: Joseph El Youssef - K23 Award Application The title of this proposal is "Optimization of an Adaptive Dual Hormone External Endocrine Pancreas" and its goal is to optimize the control algorithms and other aspects of the Adaptive Proportional Derivative (APD) system, designed to help subjects with type 1 diabetes achieve and maintain control of their diabetes. The hyperglycemic and hypoglycemic complications of diabetes are costly and have adverse effects on personal well-being and workplace efficiency. For these reasons, prevention of these complications remains an important goal of the medical community.